The major histocompatibility complex (MHC) includes a number of genes which control or regulate the immune response. Several genes in the I-region of the MHC appear to control the interaction of immunocompetent cells including the interaction of thymus-derived (T) lymphocytes with bone marrow-derived (B) lymphocytes or macrophages. In the guinea pig there seems to be a close association between I-region-associated (Ia) antigens of the MHC and immune response (Ir)genes controlling the T-cell-dependent response to certain antigens. The objective of this proposal is to further define the role of MHC antigens in immunocompetent cell interactions and their involvement in the presentation of exogenous antigens. One approach to understand the nature of the immunogenic moiety presented by macrophages to T cells will utilize small synthetic peptide antigens, responsiveness to which is under Ir gene control. The rationale is that by precisely defining the antigenic determinants involved in T-cell responses it will allow definition of how the macrophage presents the antigen and will aid in characterization of T cell recognition structures and of mechanisms of Ir gene function. Accordingly, one phase of the project will characterize macrophage handling of small peptide fragments and assess if macrophages degrade larger proteins to small immunogenic fragments, and how these processes relate to Ir gene function. A second phase will be initiated to determine the amino acid residues of small peptide antigens that directly interact with T cell antigen binding structures, and to ascertain if immune T cells can directly bind antigenic peptide fragments. Another related project will be to further characterize the regulation of Ia antigen expression in a mutant guinea pig strain (Magnum) and to assess if purified Ia anigens show exogenous antigen-binding potential.